N-alkenyltetracycline derivatives

ABSTRACT

N-ALKENYLTETRACYCLINE DERIVATIVES, FOR EXAMPLE, N-(1METHYL-2(2-THIENYL)-1-BUTENYL)TETRACYCLINE REPRESENTED BY THE FORMULA   1-((CH3-)2-N-),2,4A,5,7,11-PENTA(HO-),3-(THIEN-2-YL-   C(-C2H5)=C(-CH3)-NH-CO-),11-CH3-1,4,4A,6,11,11A,12,12A-   OCTAHYDRONAPHTHACENE-4,6-DIONE   THE COMPOUNDS GAVE EXCELLENT ANTIBACTERIAL ACTION AS COMPARED WITH TETRACYCLINE.

N-ALKENYLTETRACYCLINE DERIVATIVES Masuo Murakami, Tokyo, Masaru Iwanami, Yokohama,

"United States PatentQ Tadao Shibanuma, Asaka, Masaharu Fujimoto, Tokyo,

Norio Sato and Ryutaro Kawai, Saitama, and Kuniichiro Yano, Tokorozawa, Japan, assignors to Yamanouchi Pharmaceutical Co., Ltd., Tokyo, Japan No Drawing. Filed Dec. 6, '1971, Ser. No. 205,414 Claims priority, application Japan, Dec. 9, 1970,

45/109,160; Dec. 26, 1970, 45/128,347

Int. Cl. C07c 103/19 US. Cl. 260-559 AT Claims ABSTRACT OF THE DISCLOSURE N-alkenyltetracycline derivatives, .for example, N-[lmethyl-2(2-thienyl)-1-butenyl]tetracycline represented by the formula The compounds have excellent antibacterial action as compared with tetracycline.

DETAILED EXPLANATION- OF THE INVENTION The present invention relates to N-alkenyltetracycline derivatives having excellent antibacterial action. More particularly, the invention relates to N-alkenyltetracycline derivative represented by the Formula II'I wherein R represents a hydrogen atom, a halogen atom, or a dimethylamino group; R represents a hydrogen atom or a methyl group; R represents a hydrogen .atomor a hydroxyl group; said R and R when combined with each other form a methylene group, R represents .a hydrogen atom or a hydroxyl group; and R R and R which may be the same or dilferent, each represent a hydrogen atom, a halogen atom, a nitro group, a cyano group, a hydroxyl group, a mercapto group, a carboxyl group, a carbamoyl group, an alkoxyl group such as methoxy and ethoxy, an aryloxy group such as phenoxy, an alkylthio group such as ethylthio, an arylthio group such as phenylthio, an alkoxycarbonyl group such as ethoxycarbonyl and t-butoxycarbonyl, an aryloxycarbonyl group such as phenoxycarbonyl, an alkylsulfonyl group such as methylsulfonyl and allylsulfonyl, an arylsulfonyl group such as phenylsulfonyl, an alkanoyl group such as acetyl and t-butyryl, an aroyl group such as benzoyl, an alkylcarbamoyl group such as ethylcarbamoyl, an

arylcarbamoyl group such as phenylcarbamoyl, an alkyl group such as a saturated alkyl group, eg, methyl, ethyl, propyl, isopropyl, isobutyl, t-butyl, amyl, and octyl and an unsaturated alkyl group, c.g., 2-propionyl and allyl, a cycloalkyl group such as a saturated cycloalkyl group, c.g., cyclohexyl, cycloheptyl, etc., and an unsaturated cycloalkyl group, c.g., cyclohexenyl and indenyl, an aryl group such as phenyl and naphthyl, an aralkyl group such as benzyl, phenethyl, and Z-phenylisobutyl, and a heterocyclic ring group such as pyridyl, pyrimidyl, thienyl, pyranyl, pyrazolyl, furyl, thiazolyl, and chromanyl.

Two members of the groups R R and R may combine to form an alkylene group such as a saturated alkylene group, c.g., trimethylene, tetramethylene, pentamethylene, etc.; an unsaturated alkylene group, c.g., butenylene, etc.; a heteroatom-containing saturated alkylone group, c.g., 2-azatetramethylene 2 thiatrimethylene (CH- S-CH 2 oxatetramethylene (CI-I O-CH OH l-aza-S-oxatetramethylene (-NI-I-CH -OOH etc., and a beteroatom-containing unsaturated alkylene group, e.g., 1-oxa-2-butenylene (OCH=CHCH etc. Furthermore, each of the groups R R and R may have, as a substituent, a halogen atom, a nitro group, a cyano group, an amino group, a dimethylamino group, an imino group, a hydroxyl group, a mercapto group, a formyl group, a carboxyl group, a sulfone group, a methoxy group, a butoxyl group, a methylthio group, a phenoxy group, a phenylthio group, a methoxycarbonyl group, an ethoxycarbonyl group, a phenoxycarbonyl group, a methylsulfonyl group, a phenylsulfonyl group,

p a p-toluenesulfonyl group, an acetyl group, a benzoyl group, a furyl group, or a thienyl group and further other groups except alkyl, cycloalkyl, and alkylene shown by the groups R R and R may have the above substituent or a methyl group, an ethyl group, a butyl group, an isobutyl group, a t-butyl group, an allyl group, a cyclohexyl group, a tetramethylene group, a butadienylene (CH=CIHOH=OH), a 3-ethylbutadienylene C3115 (-on=on-o=onetc.

, The compounds of this invention represented by the Formula III are compounds that have never been reported in any references and are valuable antibiotics having excellent antibacterial power which are eflfective not only against grampositive and gramnegative bacteria but also to tetracycline resisting bacteria.

The compounds of this invention represented by the Formula III are prepared by the reaction of the tetracycline represented by the Formula I CH; CH;

3 Y. 1 4 wherein R R R and R have the same significance as growth was not observed was denoted by the results in the Formula III with the enamine compound reprebe ing shown in Table I. sented by the Formula II i TABLE I Ra Ra e 5 Concentration of sample l Orga (meg/ml.) Compounds nisms 25 6,25 1.56 0.39 0.09 R0 B7 (In Tetracycline A Product of Example: "B wherein R R and R have'the same significance as in 2 g I i i the Formula III and R and R which may be same or dilferent, each represents an alkyl group such as methyl, 5 p, i ethyl, propyl, isobutyl and t-butyl or an aryl group such as phenyl, said R and R may combine with a nitrogen Q I I i atom to form a heterocyclic ring, which may contain a heteroatom, such as a piperidine ring, a pyrrolidine ring;

----- 1' a morpholine ring, or a quinoline ring. 7

It is not known that the enarnine compound having g I i ian acid amide structure as the compound of the Formula I III is obtained by the reaction of the compound having 18 g i i a carbamoyl structure as the compound of the Formula I W with the enamine type compound as the compound of 1 "g I i Formula II, that is, such a reaction is a novel reaction 27 A discovered first by the inventors. v B i Examples of the tetracyclines represented by the above I V p Formula I, which is used as a starting-material in the ""'"f' "f""% I i aforesaid reaction. includes, e.g., tetracycline, 5-oxytetra- 29 A I cycline, 7-chlorotetracycline, 7-bromotetracycline, 5-oxy- B i 7-chlorotetracycline, 6-deoxy-5-oxytetracycline, 6-deoxy- 30 36 A 1 tetracycline, 6-deoxy-G-demethyltetracycline, 6-demethy1- B I i i tetracycline, 6 demethyl 7 chlorotetracycline, 6-methyl- 38 A enetetrac'ycline, 6-methylene-S-oxytetracycline, 5-oxy'6- B I I I i demethyltetracycline, and 7dimethylamino-6-demethyl-6- 42 p A deoxytetraeycline. 3 I= i Among the enamine compounds shown by the Formula 43 A II, there may be included novel compounds and they may B 1' be prepared by the reaction of corresponding ketones and 44 g A amines (see; Enamines written by A. Gilbert Cook, :5, "Z"'*-" B published by Marcel Dekker Co. in 1969). 45 A U The reaction of preparing the compounds of this invention is conducted by reacting the tetracycline of the Forr mula I and an equimolar to excessive molar amount, I B 4. preferably about twice by mol that of the enamine com- 53 A t pound of the Formula II in an organic solvent such as 45 T B dimethyl formamide, and the like. The reaction is con- A ducted at room temperature or under cooling or heating but is ordinarily conducted at room temperature in the 68 A presence of a mineral acid such as hydrochloric acid, B i hydrobromic acid, etc., with stirring for a few hours. In this 59 69 A case, however, a mineral acid salt of the tetracycline I and/or a mineral acid (immonium salt) of the enamine 7o A Compound II may be used in place of the mineral acid. B The desired Compounds III of this invention thus pre- 73 A pared may be isolated from the reaction product liquid B by an ordinary chemical operation such asex r n, 75 A etc., and if necessary, the product may be further purified B by reprecipitation, recrystallization and the like. 78 A In the following experiments, the antibacterial. actions B I of the compounds of this invention to a standard strain 60 83 .i A g and a tetracycline resisting bacterium were compared with I i B Y lhOSC Of tetracycline. ""f g i- EXPERIMENT I A 4 L .1 I B To an ordinary agar culture medium (pH 7) contain- -87 A ing 25, 6.25, 1.56, 0.39 or 0.9 meg/ml. of the test sample B was inoculated (A) a standard strain, Staphylococcus 88 g aureus FDA 209p or (B) a tetracycline resisting bac- 7 teria, Straplzylococcus aureus Onuma by an agar dilution 0 I 89 7 f I I I .1: i method and when the bacterium was cultivated for 24 v I hours at C-, t Was ObSl'Ved Whether the bacterium i grew or not. The case where the growth of the bacterium g1 A was obtserved w s enoted by and the case where the 75 a i TABLE IContinued Concentration of sample (mcg./ml.) Orga- Compounds nisms 6.25 1.56 0.39 0,09

10 A a B 21 A I B 0 A is B As is clear from Table I, the compounds of this invention have excellent antibacterial activity with respect to the tetracycline resisting bacterium.

In the following experiment, the antibacterial spectra of the compounds of this invention were compared with those of tetracycline.

EXPERIMENT II To a heart infusion agar culture medium containing 100, 50, 25, 12.5, 6.25, 3.13 or 1.56 meg/ml. of the test sample was inoculated (A) Sta hylococcus aureus FDA 209p, (B) Staphylococcus aureus Onama, (C) Staphylococcus aureus Shimanishi, (D) E. 0011', (E) Proteus vulgaris, (F) Pseudomonas aeroginosa, (G) Salmonella typlli H90lW, or (H) S/zigella somzei II 37148 and then bacterium was cultivated for 24 hours at 37 C. It was observed whether the bacterium grew or not. The case where the growth of the bacterium was observed was denoted by and the case where the growth was not observed was denoted by the results being shown in Table II.

Concentration of sample (meg/ml.)

Compounds msms 50 25 12.5 6.25 3.13 1.56

Tetracycline A B g E F G H Product of Example 17 A B C D E F G H Product of Example 1% A B C D a 1 i i i G H As clear from the above results shown in the Table II, the compounds of this invention had broad anti-bacterial spectra.

The invention will now be illustrated in and by the following examples. a

EXAMPLE 1 In 7 ml. of dimethylformamide was dissolved 1.0 g. of tetracycline hydrochloride and after adding to the solution 0.7 g. of a mixture of 3-methyl-2-piperidino-2- butene and 3-methyl-2-piperidino-l-butene, the mixture was stirred for 4 hours at room temperature. After the reaction was over, the solvent was distilled away from the reaction product liquid and water was added to the residue to a form a precipitate, which was recovered by filtration. The precipitate thus recovered was dissolved in 20 ml. of chloroform, the solution was washed with water, 2% aqueous acetic acid solution, and then water, and after drying the solution over anhydrous sodium sulfate, chloroform was distilled away.

Petroleum ether was added to the residue and the crystalline powder of N-(1,2-dimethyl-1-propenyl)tetracycline thus precipitated was recovered by filtration. The amount of the product was 0.5 g.

Elemental analysis as 0 11 51 0 Culculated (percent): C, 63.27; H, 6.29; N, 5.47. Found (percent): C, 63.36; H, 6.29; N, 5.46.

EXAMPLE 2 In 10 ml. of dimethylformamide was dissolved 1.0 g. of tetracycline hydrochloride and after adding to the solution 0.895 g. of l-phenyl-Z-piperidino-l-butene, the mixture was stirred for 4 hours at room temperature. After the reaction was over, the solvent was distilled away from the reaction product liquid and after adding water to the residue, the product was extracted with chloroform.

The chloroform was distilled away, ether and petroleum ether were added to the residue, and the pre cipitate thus formed was recovered by filtration. The precipitate was dissolved in chloroform, the solution was then washed with a 2% aqueous acetic acid solution and then with water, and chloroform was distilled away. When an ether-petroleum ether solvent was added to the residue followed by purification, about 1.0 g. of N-(1-ethyl-2- phenylethenyl)tetracycline was obtained. However, the product contained a small amount of a hydrogen rearrangement product, N (1 benzyl-l-propenyl)tetracycline.

Elemental annalysis as C H N O Calculated (percent): C, 66.89; H, 5.96; N, 4.87. Found (percent): C, 66.53; H, 5.92; N, 4.89.

EXAMPLE 3 In 5.5 ml. of dimethylformamide was dissolved 0.8 g. of tetracycline hydrochloride and after adding to the solution 0.7 g. of 1-(4-methylthiazole-2-yl)-2-pipe1idinopropene, the mixture was heated to 70 C. for 3 hours. After the reaction was over, the solvent was distilled away under a reduced pressure and after adding to the residue ml. of water, the product was extracted with chloroform. After washing the extract with 2% aqueous acetic acid solution and then 2% aqueous sodium bicarbonate solution, the solution was distilled away and then ml. of ether was added to the residue to form a precipitate, which was recovered by filtration to provide 0.8 g. of a yellow powder of N-[1-methyl-2-(4-methylthiazole-2-yl) ethenyl]tetracycline having a melting point of ISO-157 C. (decomposed).

Elemental analysis as C H N O S.H O. Calculated (percent): C, 58.09; H, 5.55; N, 7.01; S, 5.35. Found (percent): C, 57.74; H, 5.28; N, 6.75; S, 5.24.

EXAMPLE 4 In 5 ml. of dimethylformamide was dissolved 0.7 g. of tetracycline hydrochloride and after adding to the solution 0.7 g. of l-(2,4-dimethylpyrimidine-6-yl)-2-piperidinopropene, the mixture was heated to 70 C. for 4 hours. After the reaction was over, the solvent was distilled away from the reaction product liquid under a reduced pressure and after adding to the residue 5 ml. of water, the productwas extracted by chloroform. After washing the extract with 2% aqueous acetic acid solution and then 2% aqueous sodium bicarbonate solution, the solvent was distilled away and then 10 ml. of ether was added to the residue to form a precipitate, which was recovered by filtration to provide 0.3 g. of N-[l-methyl- 2- (2,4-dimethylpyrirnidine-6-yl)ethenyl] tetracycline having a melting point of 154-l62 C. (decomposed).

Elemental analysis as C 'H N O -H O. Calculated (percent): C, 61.17; H, 5.97; N, 9.21. Found (percent): C, 61.08; H, 5.70; N, 9.13.

EXAMPLE 5 In 14 ml. of dimethylformamide was dissolved 2.0 g. of tetracycline hydrochloride and after adding further to the solution 2.1 g. of 2-morpholino-2-undecane, the mixture was stirred for 15 hours at room temperature. After the reaction was over, the solvent was distilled away from the reaction product liquid and after adding water to the residue, the product was extracted with chloroform. The extract was washed with water, 2% aqueous acetic acid solution, 2% aqueous sodium bicarbonate solution, and then water, and after drying over anhydrous magnesium sulfate, the solvent was distilled away under a reduced pressure and ether and petroleum ether were added to the residue, thereafter the precipitate thus formed was recovered by filtration to provide 0.5 g. of N-( 1- methyl-l-decenyl)-tetracycline.

Elemental analysis as C H N O Calculated (percent): C, 66.42; H, 7.48; N, 4.70. Found (percent): C, 66.51; H, 7.25; N, 4.58.

EXAMPLE 6 In 7 ml. of dimethylformamide was dissolved 1.0 g. of tetracycline hydrochloride and after adding to the solution 1.1 g. of 1-p-nitrophenyl-2-morpholino-l-propene, the mixture was stirred for 14 hours at room temperature. After the reaction was over, the solvent was distilled away under a reduced pressure and after adding water to the residue, the product was extracted with chloroform. The extract was washed with water, 2% aqueous acetic acid solution, 2% aqueous sodium bicarbonate solution, and then water and after drying over anhydrous magnesium sulfate, the solvent was distilled away under a reduced pressure. Ether and petroleum ether were added to the residue and the precipitate thus formed was recovered by filtration to provide 0.8 g. of N-[Z-(onitrophenyl -1-methy1ethenyl]-tetracycline.

Elemental analysis as C H N O Calculated (percnt): C, 61.48; H, 5.16; N, 6.94. Found (percent): C, 61.23; H, 5.28; N, 6.72.

EXAMPLE 7 7' 4.2 (1H)(CDCl Elemental analysis as C H N O -H O. Calculated (percent): C, 62.62; H, 7.06; N, 6.85. Found (percent): C, 62.50; H, 6.77; N, 6.56.

EXAMPLE 8 In 10 ml. of dimethylformamide was dissolved 1.0 g. of tetracycline hydrochloride and after adding to the solution 0.7 g. of N-cyclohexenylpyrrolidine, the mixture was stirred for 5 hours at room temperature. After the reaction was over, the solvent was distilled away from the reaction product liquid under a reduced pressure and when water was added to the residue thus obtained and the pH of the solution was adjusted to 5 with 1 N hydrochloric acid, a precipitate was formed. The precipitate recovered by filtration was washed with water, and dis solved in chloroform, and reprecipitated from chlorofcl rm-ether to provide 0.3 g. of N-cyclohexenyltetracyc me.

EXAMPLE 9 In 10 ml. of dimethylformamide was dissolved 1.0 g. of tetracycline hydrochloride and after adding 0.7 g. of N-4-methylcyclqhexenylpiperidine to the solution, the mixture was stirred for 5 hours at room temperature. After the reaction was over, the solvent was distilled away from the reaction product liquid under a reduced pressure and when water was added to the residue thus obtained, a precipitate was formed. The precipitate was recovered by filtration and washed with water to provide Oil] g. of N-4-methylcyclohexenyltetracycline piperidine sa t.

Nuclear magnetic resonance: alkene hydrogen (Jib...)

r 3.9 (1H)(CDCI EXAMPLE 10 In 14 ml. of dimethylformamide was dissolved 1.45 g. of chlorotetracycline hydrochloride and after adding dropwise to the solution of 0.93 g. of l-piperidino-cyclohexene, the mixture was stirred for hours at room temperature. After the reaction was over, the solvent was distilled away from the reaction product liquid under a reduced pressure and when water was added to the residue thus obtained, a solid product was precipitated. The precipitate was recovered by filtration, and after drying reprecipitated from chloroform-ether to provide 0.4 g. of N-cyclohexenylchlorotetracycline.

Nuclear magnetic resonance: Alkene hydrogen 'r 3.88 (1H)(CDCl Elemental analysis as C H N O CL. Calculated (percent): C, 60.16; H, 5.59; N, 5.01; Cl, 6.34. Found (percent): C, 59.71; H, 6.01; N, 5.40; Cl, 6.00.

EXAMPLE 1 1 In 2.5 ml. of dimethylformamide was dissolved 213 mg. of 6-methylenetetracycline hydrochloride and after adding to the solution 165 mg. of N-cyclohexenyl piperidine, the mixture was stirred for 3 hours at room temperature. After the reaction was over, piperidine hydrochloride thus precipitated was filtered off and 7 ml. of methanol was added to the filtrate, whereby crystalline N-cyclohexenyl-6-methylenetetracycliue was precipitated. The amount of the product was 183 mg. The product was recovered by filtration and purified by recrystallizing from dimethylformamide-methanol.

Nuclear magnetic resonance: Alkene hydrogen (Eli 1- 4.0 (1H)(CDCl Elemental analysis as C H N O Calculated (percent): C, 66.39; H, 5.97; N, 5.53. Found (percent): C, 65.97; H, 6.21; N, 5.75.

EXAMPLE 12 In ml. of dimethylformamide was dissolved 1.0 g. of tetracycline and after adding to the solution 0.74 g. of

-cyclohexylidene piperidinium perchlorate, the mixture was stirred for 4 hours at room temperature. Then, 0.192 g. of piperidine was added to the solution and mixture was further stirred for 4 hours. After the reaction was over, the solvent was distilled away from the reaction product liquid under a reduced pressure and after adding 15 ml. of water to the residue obtained, the product was extracted twice each with 15 ml. of chloroform. After washing the extract with water, the extract was concentrated and mixed with ether and petroleum ether, whereby a precipitate was formed. The precipitate was dissolved in chloroform and after washing the solution with 2% aqueous acetic acid solution and water, ether and then petroleum ether were added to the solution, whereby a precipitate was formed. The precipitate was recovered by filtration and dissolved in a small amount of chloroform and after adding ether and petroleum ether to the solution, the product was reprecipitated to provide 0.1 g. of N-cyclohexenyltetracycline.

Nuclear magnetic resonance: Alkene hydrogen 1- 4.0 (1H) (CDCl Elemental analysis as C H N O Calculated (percent): C, 64.11; H, 6.15; N, 5.34. Found (percent): C, 53.99; H, 6.04; N, 5.27.

EXAMPLE 13 In 7 ml. of dimethylformamide was dissolved 1.0 g. of tetracycline hydrochloride and after adding to the solution 1.0 g. of N-cyclohexenylmorpholine, the mixture was stirred for 14 hours at room temperature. After the reaction was over, the solvent was distilled away under a reduced pressure, water was added to the residue obtained, and the solid precipitated was extracted with chloroform. The extract was washed with water, 2% aqueous acetic acid solution, 2% aqueous sodium bicarbonate solution, and then water and then after drying the extract over anhydrous magnesium sulfate, the solvent was distilled away under a reduced pressure. Then, ether and petroleum ether was added to the residue and the crystalline powder thus precipitated was recovered by filtration to provide 0.5 g. of N-cyclohexenyltetracycline.

Nuclear magnetic resonance: Alkene hydrogen -r 4.0 (1H) (CDCl EXAMPLE 14 In 10 ml. of dimethylformamide was dissolved 1.0 g. of tetracycline hydrochloride and after adding 1.0 g. of N-(Z-phenylcyclohexenyl)piperidine to the solution, the mixture was stirred for 5 hours at room temperature. After the reaction was over, the solvent was distilled away from the reaction product liquid under a reduced pressure and the residue was mixed with chloroform. The mixture was stirred and after filtering otf insoluble matters, the remaining solution was washed with 3% aqueous acetic acid solution and then water and after drying the solution over anhydrous magnesium sulfate, the solvent was distilled away under a reduced pressure. Then, ether-petroleum ether (1:5 in volume ratio) was added to the residue and the crystalline solid thus precipitated was recovered by filtration to provide mg. of N-(2-phenylcyclohexenyl) tetracycline.

Elemental analysis as C H O N -H O. Calculated (percent): C, 66.01; H, 6.19; N, 4.53. Found (percent): C, 65.85; H, 6.24; N, 4.43.

EXAMPLE 15 In 48 ml. of dimethylformamide was dissolved 4.88 g. of tetracycline hydrochloride and after adding to the solution 4.35 g. of N(3,4-dihydro-2-naphthyl)piperidine, the mixture was stirred for 16 hours at 60 C. After the reaction was over, the reaction product liquid was concentrated under a reduced pressure and the residue dissolved in chloroform followed by washing four times with water. When the chloroform layer thus formed was concentrated under a reduced pressure and mixed with ether, a precipitate was formed. The precipitate was recovered by filtration, dissolved in chloroform, and the solution was washed twice with 2% aqueous acetic acid solution and dried over anhydrous magnesium sulfate. Then, the solution was concentrated under a reduced pressure, ether was added to the concentrate, and the precipitate thus formed was recovered by filtration to provide 2.2 g. of N(3,4- dihydro-Z-naphthyl tetracycline.

11 Elemental analysis as C H N O Calculated (percent): C, 67.12; H, 5.63; N, 4.89. Found (percent): C, 66.90: H .91; N, 5.00.

EXAMPLE 16 In 18 ml. of dimethylformamide was dissolved 2 g. of tetracycline hydrochloride and after adding 1.91 g. of 2 piperidino 3 p tolyl 2 butene, the mixture was stirred for about 6 hours at room temperature. After the reaction was over, the solvent was distilled away from the reaction product liquid under a reduced pressure and when ether and petroleum ether was added to the residue, a precipitate was formed. The precipitate was recovered by filtration, dissolved in chloroform, after washing the solution with 2% aqueous acetic acid solution and then water, the solution was concentrated, and then ether and petroleum ether were added to the solution, whereby a precipitate was formed. The precipitate was recovered by filtration, dissolved in chloroform, and after adding ether and petroleum ether to the solution, the product was reprecipitated to provide 2 g. of N-(1-methyl-2-ptolyll-propenyl tetracycline.

Elemental analysis as C H N O Calculated (percent): C, 67.33; H, 6.16; N, 4.76. Found (percent): C, 67.22; H, 6.43; N, 4.95.

EXAMPLE 17 In 18 ml. of dimethylformamide was dissolved 2 g. of tetracycline hydrochloride and after adding to the solution 2.03 g. of 3-methyl-3-p-tolyl-2-piperidino-l-butene, the mixture was stirred for about 6 hours at room temperature. Thereafter, by following the same procedure as in Example 16, 2 g. of N-[1-(1-methyl1-p-tolylethyl) ethenyl]-tetracycline was obtained.

Elemental analysis as C H N O Calculated (percent): C, 67.76; H, 6.36; N, 4.65. Found (percent): C, 67.69; H, 6.33; N, 4.80.

EXAMPLE 18 In 18 ml. of dimethylformamide was dissolved 2 g. of tetracycline hydrochloride and after adding to the solution 1.8 g. of l-(2-furyl)-2-morpholino-l-propene, the mixture was stirred for about 6 hours at room tempera ture. Thereafter, by following the same procedure as in Example 16, 0.2 g. of N-[1-methyl-2-(2-furyl)-ethenyl] tetracycline was obtained.

Elemental analysis as C29H3oN209. Calculated (percent): C, 63.27; H, 5.49; N, 5.09. Found (percent): C, 63.55; H, 5.75; N, 4.91.

EXAMPLE 19 In 7 ml. of dimethylformamide were dissolved 1 g. of

tetracycline hydrochloride and 1 g. of N-(6 ethyl-3,4- dihydro 2 naphthyl)piperidine and the solution was heated for 5 hours at 80 C. After the reaction was over, the solvent was distilled away from the reaction product liquid under a reduced pressure and after adding 5 ml. of water to the residue, the product was extracted with chloroform. The extract was washed with 2% aqueous acetic acid solution and then 2% aqueous sodium bicarbonate solution and after drying over anhydrous magnesium sulfate, the solvent was distilled away from the extract. Then, ml. of ether was added to the residue, the powder precipitated was recovered by filtration, and reprecipitated from chloroform-ether to provide 0.6 g. of N-(6-ethyl 3,4 dihydro 2 naphthyl)tetracycline having a melting point of 172l76 C.

Elemental analysis as C H N O Calculated (percent): C, 67.99; H, 6.04; N, 4.66. Found (percent): C, 67.86; H, 5.87; N, 4.78.

EXAMPLE In 38 ml. of dimethylformamide was dissolved 3.80 g. of tetracycline hydrochloride and after adding to the solution 3.17 g.-.of N-(2-indenyl)piperidine, the mixture was stirred for 16 hours at 60 C. After the reaction was over, the reaction product liquid was concentrated under a reduced pressure, dissolved in chloroform, and washed thrice with water. Insoluble matters precipitated were filtered-off. The chloroform layer was then concentrated under a reduced pressure and ether-n-hexane (1:10 in volume ratio) solvent mixture was added to the concentrate, whereby a precipitate was formed. The precipitate was recovered by filtration, dissolved in a small amount of chloroform, and ether was added to the solution, whereby a precipitate was formed. The precipitate was recovered by filtration, dissolved in chloroform, and the solution was washed with 2% aqueous acetic acid solution and then water. After drying the solution over anhydrous magnesium sulfate, the solution was concentrated under a reduced pressure and an ethern-hexane (1:10 in volume ratio) solvent mixture was added to the concentrate to form a precipitate, which was recovered by filtration to provide 0.3 g. of N-( 2-indeny1)- tetracycline.

Elemental analysis as C H N O Calculated (per cent): C, 66.65; H, 5.41; N, 5.02. Found (percent): C, 66.38; H, 5.66; .N, 5.16.

EXAMPLE 21 In 7 ml. of dimethylformamide was dissolved 0.8 g. of 5-oxytetracycline and after adding to the solution 0.9 g. of 3-methyl-2-piperidino 3 p tolyl l butene and further 0.27 ml. of 6.5 N aqueous hydrogen chloride in dimethylformamide, the mixture was stirred for 4 hours at room temperature. After the reaction was over, the reaction product liquid was concentrated under a reduced pressure and after adding 10 ml. of water, the product was extracted twice eachwith 30 ml. of chloroform. The extract was washed with water, 2% acetic acid solution, and then water and after drying over anhydrous magnesium sulfate, the solvent was distilled away from the extract under .a reduced pressure. Then, ether and petroleum' ether were added to the residue and the crystallme powder thus formed was recovered by filtration. The product was reprec'ipitated from chloroform to provide 0.4 g. of N-[1-(1methyl-1-p-tolylethyl)ethenyl] 5 oxytetracycline.

Elemental analysis as C H N O Calculated (percent): C, 66.01; H, 6.19; N, 4.53. Found (percent): C 65.89; H, 6.35; N, 4.70. I

EXAMPLE 22 In 13 m1. of dimethylformamide was dissolved 1.3 g. of 6-dimethyl-7-chlorotetracycline hydrochloride and after adding to the solution 1.26 g. of 3-rncthyl-2-piperidino-3-p-tolyl-1-butene, the mixture was stirred for 6 hours atroorn temperature. Thereafter, by following the same procedure as .in Example 16, 0.8 g. of N-[1-(1- methyl-l-p-tolyl-ethyDethenyl] 6 di'methyl-7-chlorotetracycline was obtained.

Elemental analysis as C H N O Cl. Calculated (percent): C, 63.61; H, 5.66; N, 4.50; Cl, 5.69. Found (percent): C, 63.30; H, 5.74; N, 4.57; Cl, 5.60.

EXAMPLE 23 In 13 ml. of dimethylformamide was dissolved 1.2 g. of 7-chlorotetracycline hydrochloride and after adding to the solution 1.14 g. of 3-methyl-2-piperidino-3-p-toly1- l-butene, the mixture was stirred for 6 hours at room temperature.' Th'ereafter, by following the same procedure as in Example 16, 0.5 g. of N-[l-(l-methyl-l-p-tolylethyl)ethenyl]-7-chlorotetracycline was obtained.

13 Elemental analysis as C H N O Cl. Calculated (percent): C, 64.10; H, 5.86; N, 4.40; Cl, 5.56. Found (percent): C, 63.94; H, 5.79; N, 4.54; Cl, 5.52.

EXAMPLE 24 EXAMPLE 25 In ml. of dimethylformamide was dissolved 430 mg.

of tetracycline hydrochloride and after adding to the solution 560 mg. of 1-p-methylsulfonylphenyl-Z-morpholino-l-propene, the mixture was stirred for 24 hours at room temperature. Thereafter, by following the same procedure as in Example 21, 120 mg. of N-(l-methyl-Z- p-methylsulfonylphenylethenyl)tetracycline was obtained.

Elemental analysis as C H ,N O S. Calculated (percent): C, 60.18; H, 5.37; N, 4.39. Found (percent): C, 59.80; H, 5.32; N, 4.04.

EXAMPLE 26 In 5 ml. of dimethylformamide was dissolved 477 mg. of tetracycline hydrochloride and then after adding 338 mg. of N-(4,5-dihydro-3-thienyl)piperidine to the solution, the mixture was stirred for 7 hours at room tempera ture. After the reaction was over, the solvent was distilled away from the reaction product liquid under a reduced pressure, water was added to the residue thus obtained, and the crystal formed was recovered by filtration to provide 353 mg. of N-(dihydro-3-thienyl)tetracycline.

In addition, the filtrate was extracted with chloroform and the extract was washed with water, dried over anhydrous sodium sulfate, the solvent was distilled away under a reduced pressure, the residue thus obtained was dissolved in acetone, and ether was added to the solution to form a precipitate, which Was recovered by filtration to provide 23 mg. of N-(4,5-dihydro-3-thienyl)tetra-' cycline.

Elemental analysis as C H O N S. Calculated (per cent): C, 59.08; H, 5.34; N, 5.30; S, 6.07. Found (percent): C, 60.03; H, 5.00; N, 5.33; S, 5.86.

EXAMPLE 27 In ml. of dimethylformamide was dissolved 2.0 g. of 6-dimethyl-7-chlorotetracycline hydrochloride and after adding to the solution 1.83 g. of a mixture of 2- piperidino-3-p-tolyl-l-butene and 2-piperidino-3-p-tolyl-2- butene, the mixture was stirred for 6 hours at room temperature.

Thereafter, by following the same procedure as in Example 26, 1.0 g. of the light yellow powder of N-[l-(lp tolylethyl)ethyl]-6-dimethyl 7 chlorotetracycline was obtained.

Elemental analysis as C H N O CI. Calculated (percent): C, 63.10; H, 5.46; N, 4.60; Cl, 5.82. Found (percent): C, 62.81; H, 5.33; N, 4.78; Cl, 6.01.

EXAMPLE 28 In 12 ml. of dimethylformamide was dissolved 1.5 g. of tetracycline hydrochloride and after adding to the solution 2.0 g. of 2-morpholino-3-(Z-thienyl)-2-pentene, the mixture was stirred for 6 hours at room temperature.

After the reaction was over, the solvent was distilled away from the reaction product liquid under a reduced pressure and after adding water and chloroform to the residue fol-lowed by sulficient shaking, the chloroform layer formed was recovered. The extract was washed with 2% aqueous acetic acid solution and then water and after drying over anhydrous magnesium sulfate, the solvent was distilled away under a reduced pressure. When ether and petroleum ether were added to the residue, a precipitate was formed, which was recovered by filtration and dissolved in chloroform. When ether and petroleum ether were added to the solution and the product was reprecipitated, 1.0 g. of the light yellow powder of N- [1-methyl-2-(2-thienyl)-1-buteny11tetracycline was obtained.

Elemental analysis as C H N O S. Calculated (percent): C, 62.61; H, 5.76; N, 4.71; S, 5.39. Found (percent): C, 62.75; H, 5.82; N, 4.96; S, 5.52.

EXAMPLE 29 In 40 ml. of dimethylformamide was dissolved 5.5 g. of tetracycline hydrochloride and after adding to the solution 6.0 g. of 3-methyl-2-morpholino-3-(2-thienyl)-1- butene, the mixture was stirred for 7 hours at room temperature. Thereafter, by following the same procedure as in Example 28, 4.0 g. of the light yellow powder of N-[l-(l-methyl-l-(Z thienyl) ethyl) ethenyl]tetracycline was obtained.

Elemental analysis as C H N O S. Calculated (percent): C, 62.61; H, 5.76; N, 4.71; S, 5.39. Found (percent): C, 62.69; H, 5.98; N, 4.51; S, 5.48.

EXAMPLE 30 In 2.5 ml. of dimethylformamide was dissolved 255 mg.

. of tetracycline hydrochloride and after adding to the solution 350 mg. of crude l-cyclohexyLZ-morpholino-l-propene, the mixture was stirred for 5 hours at room temperature. After the reaction was over, the reaction product liquid was concentrated under a reduced pressure and after adding a small amount of water to the concentrate, the product was extracted with chloroform. The extract was Washed with water, twice with 2% aqueous acetic acid s lution, and then thrice with water and after drying over anhydrous magnesium sulfate, the extract was concentrated under a reduced pressure to such an extent that a small amount of chloroform remained. When ether and petroleum ether was added to the concentrate, a precipitate was formed. The precipitate was recovered by filtration, dissolved in a small amount of chloroform, and after adding ether and petroleum ether, the product was reprecipitated, whereby mg. of the yellow powder of N-(2- cyclohexyl-l-methylethenyl)tetracycline was obtained.

Elemental analysis as C H N 0 Calculated (percent): C, 65.71; H, 6.76; N, 4.94. Found (percent): C, 65.50; H, 6.92; N, 5.11.

EXAMPLE 31 EXAMPLE 32 To 7 ml. of dimethylformamide were added 1 g. of

l,Z-dipiperidino-l-propene and l g. of tetracycline hydrochloride under ice-cooling and the mixture was stirred for 15 2 hours in an ice-water bath. After the reaction was over, the solvent was distilled away from the reaction product liquid under a reduced pressure and after adding 10 ml. of water to the residue, the product was extracted thrice each with 5 ml. of chloroform. The chloroform extract was then extracted with 2% aqueous acetic acid solution until the aqueous layer became acidic. To the extract was added sodium bicarbonate to adjust the pH thereof to about 7.5 and after washing the extract with ml. of

EXAMPLES 3548 By the same way as above, the following compounds shown by the formula were prepared.

CHa CH1 OHa OH N R5 R5 CONH J-C p OH R1 OH Elemental analysis (percent) Calculated Found Number of example R R5 R 0 H N C H N CH; -H G Cl 58.55 4.59 5.55 58.32 4.37 4.8]. 36 CH; -H Q 01 57.50 4.98 4.33 57.68 5.09 4.55

37- CH; H CH: 65.66 6.18 6.96 65.30 6.32 6.73

38 CH2CH2S-CH2 H 59.77 5.10 5.16 59.44 6.00 5.46

ether, the product was extracted thrice each with 10 ml. EXAMPLE 39 of chloroform. When the chloroform was distilled away from the chloroform extract under a reduced pressure and n-hexane was added to the residue, a powder was precipitated. The powder was recovered by filtration to provide 0.7 g. of N-(1-methyl-2-piperidinoethenyl)tetracycline.

Elemental analysis as C H N O Calculated (percent): C, 63.48; H, 6.57; N, 7.40. Found (percent): C, 63.26; H, 6.63; N, 7.23.

EXAMPLE 33 In 10 ml. of dimethylformamide was dissolved 1.05 g. of tetracycline hydrochloride and after adding to the solution 1.2 g. of 1-(2-quinolyl)-2-piperidino-l-propene, the mixture was stirred for 5 hours at room temperature. After the reaction was over, the reaction product liquid was concentrated under a reduced pressure and after adding water to the concentrate, the product was extracted with chloroform. The extract was washed with water, 2% aqueous acetic acid solution, and then water and after drying over anhydrous sodium sulfate, chloroform was distilled away. When ether and petroleum ether were added to the residue, a precipitate was formed. The precipitate was recovered by filtration and dissolved in a small amount of chloroform. Then, ether and petroleum ether were added followed by reprecipitation to provide 0.2 g. of N-[lmethyl-Z- (2-quinolyl ethenyl] tetracycline.

Elemental analysis as C H N O Calculated (percent): C, 66.77; H, 5.44; N, 6.87. Found (percent): C, 66.33; H, 5.64; N, 7.00.

EXAMPLE 34 In 13 ml. of dimethylformamide was dissolved 1.904 g. of tetracycline hydrochloride and after adding 1.224 g. of 3-piperidino-2-pentene to the solution, the mixture was stirred for 3 hours at room temperature. After the reaction was over, piperidine hydrochloride precipitated in the reaction was filtered off and the solvent was distilled away from the filtrate. When 3 ml. of water was added to the In 10 ml. of dimethylformamide was dissolved 1.0 g. of tetracycline hydrochloride and after adding to the solution 0.7 g. of N-cyclohexenylpiperidine, the mixture was stirred for 5 hours at room temperature. After the reaction was over, the solvent was distilled away from the reaction product liquid under a reduced pressure and when water was added to the residue obtained and then the pH of the solution was adjusted to 5 with 1 N hydrochloric acid, a precipitate was formed. The precipitate was recovered by filtration, dissolved in chloroform after being washed with water, and reprecipitated from chloroformether to provide 0.6 g. of N-cyclohexeneyltetracycline.

Nuclear magnetic reasonance: Alkene hydrogen -r 4.0 (1H) (CD01 Elemental analysis as C H N O -H O. Calculated (percent): C, 61.98; H, 6.32; N, 5.16. Found (percent): C, 61.58; H, 6.13; N, 5.19.

EXAMPLE 40 In 10 ml. of dimethylformamide was dissolved 1.0 g. of tetracycline hydrochloride and after adding to the solution 0.75 g. of N-cycloheptenylpiperidine, the mixture was stirred for 5 hours at room temperature. Thereafter, by following the same procedure as in Example 39, 0.65 g. of N-cycloheptenyltetracycline was obtained.

Nuclear magnetic resonance: Alkene hydrogen -r 3.8 (lH)(CDCl Elemental analysis as C H N O -H O. Calculated (percent): C, 62.58; H, 6.52; N, 5.03. Found (percent): C, 62.28; H, 6.38; N, 5.25.

EXAMPLE 41 In 10 ml. of dimethylformamide was dissolved 1.0 g. of tetracycline hydrochloride and after adding to the solution 0.8 g.- of N-cyclooctenylpiperidine, the mixture was stirred for 5 hours at room temperature. Thereafter,

by following the same procedure as in Example 39, 1.1

' g. of N-cyclooctenyltetracycline was obtained.

EXAMPLES 43-46 By the same way as above, the following compounds were prepared.

Elemental analysis (percent) Calculated Found Numberof example R5 Rn R1 0 H N C N 43- .--cmon. -H 67.33 6.16 416 67.61 an 4.49

44 -omcn. Q -CH; 67.76 6.36 4.65 can 6.71 4.23

45- =--cH2cH. -crn ems 6.36 4.65 67.284108 4.5a

4s-'-==='..====5.. -crr. 4:11.011, -H 63.27 6.29 5.47 our 6.53 5.18

Nuclear magnetic resonance: Alkene hydrogen 1' 3.9 (1H) (CDC1 Elemental analysis as C H N 0 -H O. Calculated (percent): C, 63.14; H, 6.71; N, 4.91. Found (percent): C, 63.02; H, 6.58; N, 4.72.

- EXAMPLE 42 To 5 of dimethylformamide were a dded 558 I of Z-piperidino-l-m-tolyl-l-butene and 625 mg. oftetracycline hydrochloride and then the mixture was stirred for 6 hours at room temperature.

After the reaction was over, the solvent was distilled away from the reaction product liquid under a reduced pressure and the residue obtained was extracted with EXAMPLE 47 away. The residue was dissolved in ether, and after adding petroleum ether to the solution, the precipitate formed was recovered by filtration and dried to provide 453 mg. of N- l-( l-methyll-m-tolylethyl) ethenyl] tetracycline.

Elemental analysis as C H N O Calculated (percent): C, 67.76; H, 6.36; N, 4.65. Found (percent): C, 67.39; H, 6.50; N, 4.97.

1 9 EXAMPLES 48-52 By the same way as above, the following examples were prepared.

Elemental analysis (percent) Calculated Found Number example R; R4 R1 0 H N C H N 49 on. H --H 66.23 6.67 4.41 66.02 6.51 4.07

LEIGH] 2H1 5o CH. --CH. H 67.76 6.36 4.65 67.55 e21 4.87

51 --CH| I CH; v 6133 6.16 4.76 67.83 0.01 4.77

HzCHz- EXAMPLE 53 solution. The solution was further washed thrice with In 40 ml. of dimethylformamide was dissolved 4.1 g. of tetracycline hydrochloride and after adding dropwise 4 g. of 1 (p chlorophenyl)-2-piperidinoprene to the solution at room temperature, the mixture was stirred for 5 hours at room temperature. After the reaction was over, the solvent was distilled away from the reaction product liquid under a reduced pressure and the residue was form was distilled away. When ether was added to the 55 were prepared.

ashedwithwaterand dissolved in.200 ml. of chl0ro-..

water and after drying over anhydrous sodium sulfate, chloroform was distilled away.

When ether-petroleum ether (1:3) mixture was added to the residue, 3g. of N (2 p chlorophenyl-l-methylethenyDtetracycline was precipitated.

Elemental analysis as 0 11 51 0 01. Calculated (percent): C, 62.57; H, 5.25; N, 4.71; Cl, 5.96. Found (percent): C, 62.40; H, 5.45; N, 4.80; Cl, 6.01.

' EXAMPLES 54-64 By the same way as above, the following compounds Elemental analysis (percent) Calculated Found Number of example R| R4 R1 0 H N C H N 54 -CH: ----CH: Q 66.89 6.96 4.87 67.01 6.25 4.65

55--. CH1 -H OCH;

O CH;

TABLEContlnued (Elementary analysis percent) Calculated Found Number of example R Ra R H N C H N 56 -CH: H 67.33 6.16 4.76 67.13 6.21 4.83

CHgCHI 57 --CH| --H 67.33 6.16 4.76 67.10 6.17 4.86

58 -CH1 ---H CH: 63.86 6.51 5.32 63.58 6.46 5.41

59 CH:CHaCHzCHz- CH1 64.67 6.36 5.20 64.26 6.15 5.55

60 H 66.01 are 4.53 65.99 0.13 4.24

CH=OHzCHCH I aCflr- 62 --H CH=CHCH:CH:- 62.45 5.61 5.20 62.60 5.90 5.10

CH:CHCHCH: 65.31 5.79 65.2 65.18 5.62 6.33

EXAMPLE 65 In ml. of dimethylformamide was dissolved 1.0 g. of tetracycline hydrochloride and after adding 1.15 g. of 1,1 diphenyl 2 piperidinopropene to the solution, the mixture was stirred for 7 hours at room temperature. After the reaction was over, the solvent was distilled away from the reaction product liquid under a reduced pressure and after adding water to the residue, the product was extracted with chloroform. After washing the chloroform layer a few times with water, chloroform was distilled away. When petroleum ether was added to the residue and residue, the precipitate thus formed was recovered by filtration. The precipitate was dissolved in chloroform EXAMPLES 66-95 By the same way as above, the following compounds were prepared.

CH: CH;

OH: OH N Elementary analysis (percent) Calculated Found Numberotexample Rs R1 R1 0 H N C H N 66 -.-H om Q 6642 5.75 5.00 was 5.90 4.85

67 -oH. -n 3 04.10 see us case an 1.45 68....-.*..:.;.:::;:=-CH| H Q 65.08 5.80 5.74 64.96 5.89 81.

69 CH.| H 66.89 5.96 4.87 66.72 5.07 5.20

70....-.; ---CH; H 64.35 5.40 6.84 64.12 5.47 4.00

TABLEContinued A Elementary analysis (percent) Calculated Found Number oiexnmple R R4 R C. H N C H N 90 CHI -H H 63.15 5.96 4.61 62.94 5.76 4.81

H CH:

91 CH -H H 63.65 6.15 4.50 63.38 6.00 4.70

&

HnCHzCH1 92 OH H -H 64.35 6.12 4.73 64.95 6.22 4.60

" LHzCH:

93 CH H 'H 6533 6 31 4.62 65 10 640 4 71 lHgCHzCH;

( HzhCH;

9s .-CH; CH:CH; f W 66.65 607 4.44 6638 627 4.64

-c--cm EXAMPLE 96 was washed with water, and after drying over anhydrous In 17 ml. of dimethylformamide was dissolved 1.7 g.

sodium sulfate, chloroform was distilled away. The resiof tetracycline hydrochloride and after adding dropwise due was dissolved in ether and p pi a ed 50?. n-

1.3 g. of 4-piperidino-3-heptene to the solution at room temperature, the mixture was stirred for 5 hours at room temperature. After the reaction was over, the solvent was distilled away from the reaction product liquid under a reduced pressure and water was added to the residue,

whereby a solid product was precipitated. The precipitate was recovered by filtration to provide 1.8 g. of N-(l-propyl-1-buteny1)tetracycline. The product was almost pure but the product was dissolved in chloroform, the solution hexane.

Elemental analysis as C H N O Calculated (percent): C, 64.43; H, 6.71; N, 5.18. Found (percent j: C, 64.14; H, 7.00; N, 5.60.

EXAMPLES 97-143 By the same way as above, the following compounds were prepared.

Elemental analysis (percent) Calculated Found R; R6 R1 C H N C H N H CH:CH; CH:CH; 61.75 6.66 5.14 61.32 6.81 5.60

H G 66.42 5.75 5.00 65.96 5.99 5.26 99 Q H H 62.02 5.03 4.826171 5.20 5.12

100 H -11 CH; 59.75 6.02 5.57 59.63 6.36 5.41

101 H CH; -CH; 62.64 6.07 5.62 62.52 6.19 5.81

TABLEContlnued Elemental analysis (percent) Calculated Found Number of example R1 R R; C H N C H N 104 -CH0 H Q 62. 57 5. 4. 71 62. 51 5. 4. 91

105 -CH0 -CH3 QC] 63.10 5.46 4.60 62.95 5.29 4.85

106 .r. --CH1 CH2CH=CH2 Q01 64.30 5.55 4.41 64.11 5.64 4. 75

107 -CH: -H QB 58.22 4.89 4.38 58. 01 4.95 4.58

108 OH; --H -H 63.61 5.66 4.50 63.33 5.74 4.76

109 CH| --H 0Q 64. 58 5. 59 4. 86 64. 48 5. 81 5. 05

110 CH| -H 65. 07 5. 80 4. 74 65. 30 6. 10 5. 00

' O CH:

-CHzCHr-N-CH:

112--.-.'-.-.-'--.- '-CHI -(CH CH; -H 64.97 6.91 5.05 64.81 7.66 5.13 113 "-0113 U '-'H 61.47 5.34 4.94 61.56 5.05 5.04

114 ';;.".m (in; H -H 67.33 6.16 4.76 67.13 6.16 5.01

0. 0 115 CH; 'H H 68.17 6.54 4.54 08.45 6.68 4.75

116 -CH; -CHO 67.76 6.36 4.65 67.77 6.39 4.77

- CHaCEt 117 CH: H -H 68.17 6.54 4.54 68.21 6.73 4.71

lfizc l 11s.; CH. Q -H 66.89 5.97 4.87 66.85 0.10 5.10

119........... CH: -OH. 05.55 0.00 4.63 05.00 5.00 4.00

120..-. CH. -H -H 00.01 0.19 4.50 05.00 0.22 4.10

121 -cn.cn. -cH. 01.00 0.10 4.10 01.01 0.12 0.02

122. on. H H 05.05 0.00 4.00 05.00 5.02 4.02

-0H1CH1 -CH. @4311 01.10 0.00 4.05 01.20 0.30 4.20

124 CH;CH1 -CH0CH| Sameasabove 66.16 6.54 4.54 67.68 6.61 4.71

CH; CH: 62.06 5.55 4.82 61.83 5.48 4.71 LQJ TABLE-C0nt1nu ed Elemental analysis (percent) Found Calculated Number of example -CHzCH m.. -CH:

m c. H w

c c c 63.86 5.85 4.51 63.37 5.94 4.43 SCH:

/CH: --CH\ -s oQ-cn.

Elemental analysis: Calculated (percent): C, 61.93; H, 5.64; N, 4.12. Found (percent): C, 61.81; H, 5.30; N, 4.51.

What is claimed is:

1. An N-alkenyltetracycline derivative represented b the formula wherein R represents a hydrogen atom or a halogen atom; R represents a hydrogen atom or a methyl group; R represents a hydrogen atom or a hydroxyl group or said R, and R when combined with each other, form a methyl- 32 ene group; R represents a hydrogen atom or a hydroxyl group and R is lower alkyl or trr.

R is hydrogen, phenyl, naphthyl or lower alkyl phenyl and when R and R taken together forming pentamethylene and R is hydrogen, lower alkyl or lower alkyl phenyl, the aforesaid lower alkyl groups having from 1 to 8 carbon atoms.

2. N-( l-methyl-Z-a-naphthyl-l-butenyD-tetracycline. 3. N- l-( l-methyl-l-tolylethyl) -ethenyl]-tetracycline. 4. N- 2-p-tolyll-cycloheptenyl tetracycline. 5. N-( 1-rnethyl-2-p-tolyl-l-pentenyl) tetracycline.

References Cited I UNITED STATES PATENTS 3,028,409 4/ 1962 Stephens 260559 AT ALEX MAZEL, Primary Examiner A. M. T. TIGHE, Assistant Examiner US. Cl. X.R.

260240 R, 246 B, 247.1, 247.2 A, 256.4 R, 256.5 R, 268 TR, 293.62, 294.8 A, 295 A, 303, 310 R, 326.3, 329.2, 345.3, 345.7, 347.3, 465 D, 470, 471 A, 516, 519; 424227 UNITED STATES PATENT OFFICE CERTIFICATE OF CGRRECTION Patent No. 3 808, 274 Dated April 30, 1974 KUNIICHIRO YANO Inventor(s) MASUO MU'RAKAMI, MASARU IVHXNAMI, TADAO SHIBANUMA,

MASAHARU FUJIMOIO, NORIO SATO and RYNIARO KUWAI It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

Column 7, line 6, "annalysis" should be analysis Column 16, in the Table for Example 35, the calculated N value for Example 35 is listed as 5.55", it

should be 4.55

In the same table for Example 38, the "H" value set out as "6.00" should be 6.09

Columns 21 and 22, first Table, in the elementary analysis for Example 63, the calculated N value is set out as "65.2" it should be 6.52

Second Table, Example 68, percent calculated should be 4.74 instead bf "5.74"

Example 70, the percent found is listed at "4.00"

and should be 5.00

Columns 23 and 24, Example 73, percent calculated is listed as "5.87" and this should be 4.87

UNITED STATES PATENT OFFICE CERTIFICATE OF CGRRECTIGN Patent No. 3, 0 ,274 Dated A ril 30, 1974 In entor( AL.

It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

Page 2 Columns 27 and 28, Example 124, the C calculated is shown as "66.16" and should be 68.16

Columns 29 and 30, Example 130, the N percent found is listed as "4.85" and should be 4.82

Example 131, the N percent found is listed as "4.26" and should read 4.65

Column 22, "Elementary" should read Elemental Column 32, in Claim 1, in the formula representing on e of the groups for R CH should be CH Signed and sea led this 13th day of March 1975.

(SEAL) Attest:

C. MARSHALL DANN RUTH C. MASON Commissioner of Patents Attesting Officer and Trademarks 

